Methods of administering tolperisone for therapeutic purposes

ABSTRACT

The present disclosure relates to methods of administering tolperisone to subjects in need thereof. In certain aspects, the present disclosure relates to methods of administering tolperisone to subjects in need thereof, said methods limiting the exposure of the subject to 4-MMPPO.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Divisional application from U.S.application Ser. No. 12/597,664, which is a U.S. National StageApplication of International Application No. PCT/US2008/005281, eachhaving a filing date of Apr. 24, 2008, and claiming the benefit ofpriority to Austrian Patent Application No. A 658/2007, filed on Apr.26, 2007, and Austrian Patent Application No. A 195312007, filed on Nov.29, 2007, and U.S. Provisional Application No. 61/023,799, filed on Jan.25, 2008, the contents of each of which are herein incorporated byreference.

FIELD

The present disclosure relates generally to tolperisone,2-methyl-1-(4-methylphenyl)-3-(-piperidinyl)-1-propanone), havingextremely low levels of 4-MMPPO (2-methyl-1-(4-methylphenyl)-propenone),and methods of producing the same, as well as compositions relatedthereto. The invention further relates to methods of treating a subjectwith tolperisone under conditions that limit exposure of the subject totolerable levels of 4-MMPPO, among other features.

BACKGROUND

Tolperisone is a centrally-acting muscle relaxant that has been used forthe symptomatic treatment of spasticity and muscle spasm (Martindale,The Extra Pharmacopoeia, 30th ed., p. 1211). Tolperisone has also beenused in the treatment of conditions which include dysmenorrhea,climacteric complaints, lockjaw, and neurolatyrism.

The chemical structure of tolperisone is shown below.

As can be seen by the foregoing structure, tolperisone contains a chiralcenter (as indicated by the asterisk). Racemic tolperisone iscommercially available as the hydrochloride salt and is sold under tradenames such as Mydeton®, Mydocalm®, Midocalm® and Muscalm®.

The chiral separation of tolperisone into its R(−) and S(+) enantiomershas been described (See, for example, JP-A-53-40779).

Tolperisone has been shown to exhibit membrane-stabilizing effects inthe central and peripheral nervous system (Ono, H., et al., J.Pharmacobio. Dynam. 1984, 7, 171-178). Tolperisone and its salts areused for improving not only different symptoms related to spasticparalysis, but also for improving muscle tone which originates fromdiseases or conditions such as cervical syndrome, inflammation of thejoints, and back pain. Recently, the use of tolperisone for treatingneuropathic pain and pain associated with various nervous systemdisorders has also been described (see, for example, U.S. PatentApplication No. 2006/0004050).

SUMMARY

Tolperisone can be prepared by a number of different syntheticapproaches. As recognized by the inventors, as a result of sidereactions and chemical impurities either present in the startingmaterials, or formed during the synthesis of tolperisone or over theshelf life of the formulation, current methods of producing tolperisonehave the associated drawback of producing a final product that containslevels of impurities that can be toxic to patients undergoing treatmentwith tolperisone, even when present in extremely small quantities.

In one aspect, the present disclosure addresses the need for improvedmethods of providing tolperisone having negligible levels of impuritiessuch as the genotoxic agent, 4-MMPPO. In another aspect, the presentdisclosure provides methods for treating subjects by administeringtolperisone in which exposure to genotoxic agents such as 4-MMPPO intolperisone-containing pharmaceutical compositions is minimized, amongothers.

Specifically, in at least one aspect, the disclosure is directed totolperisone comprising less than about 10 ppm2-methyl-1-(4-methylphenyl)-propanone (4-MMPPO) and compositionsthereof.

In a particular embodiment, tolperisone as provided herein comprisesless than about 7 ppm 4-MMPPO.

In yet another embodiment, tolperisone comprises less than about 3 ppm4-MMPPO.

In a preferred embodiment, provided herein is tolperisone comprisingfrom about 1.5 to 10 ppm 4-MMPPO.

Additionally, provided herein is a pharmaceutical composition comprisingtolperisone as previously described and one or more a pharmaceuticallyacceptable excipients.

In one embodiment of the foregoing, said one or more pharmaceuticallyacceptable excipients comprises an acid.

In yet another aspect, provided herein is method of preparing a purifiedcomposition of tolperisone. The method comprises the steps of (i)providing tolperisone comprising an initial level of 4-MMPPO greaterthan 10 ppm, and optionally additional impurities, and (ii) purifyingthe tolperisone to form a purified tolperisone having a level of 4-MMPPOthat is less than about 10 ppm.

In one embodiment of the foregoing method, the purifying step iseffective to reduce the level of 4-MMPPO by at least five-fold over itsinitial level.

In yet another embodiment, purified tolperisone produced by the methodhas a level of 4-MMPPO of less than about 7 ppm, for example, having apurity as described above.

The method may also further comprise, prior to the providing step,identifying the presence of 4-MMPPO as a contaminant in the tolperisone,and optionally, determining the initial level of 4-MMPPO in thetolperisone.

In an additional embodiment of the method, the purifying comprisesrecrystallization from a single solvent or a combination of solvents toprovide recrystallized tolperisone.

In another embodiment of the method, the recrystallization compriseseither one or multiple recrystallization steps.

In yet another embodiment, the recrystallization is carried out in amixed organic solvent system. In a particular embodiment, the solventsystem comprises a lower ketone and a lower alcohol. In yet anotherembodiment, the solvent system comprises 2-butanone (methyl ethylketone) and isopropanol.

In a further embodiment, the recrystallization comprises dissolvingtolperisone in an acidified solvent, optionally with heating, to form asolution of tolperisone, and allowing crystals of tolperisone to formfrom the solution.

In yet another alternative embodiment of the method, purifying comprisesa drying step. The drying step may be carried out at atmosphericpressure or under reduced pressure. Drying may be carried out at ambienttemperature or at elevated temperatures, e.g., from 30° C. to about 60°C.

In yet another aspect, provided herein is an improvement in a syntheticmethod for preparing tolperisone, where the improvement comprisesaddition of a catalytic amount of acid to thereby minimize formation of4-MMPPO.

In a particular embodiment of the foregoing improvement, the acid isanhydrous hydrogen chloride gas.

Also provided herein is purified tolperisone, and compositions thereof,produced by the foregoing methods and all and any embodiments thereof.

In yet another aspect, provided herein is an improvement in a method ofadministering tolperisone to a subject in need thereof, where theimprovement comprises administering a composition of tolperisonecomprising less than about 10 ppm 2-methyl-1-(4-methylphenyl)-propanone(4-MMPPO), e.g., from about 1.5 to about 10 ppm 4-MMPPO.

In a particular embodiment of the foregoing, as a result of theadministering, genotoxic effects of the composition related to thepresence of 4-MMPPO upon the subject are minimized.

In yet another aspect, provided herein is tolperisone comprising lessthan about 10 ppm 4-MMPPO packaged in a suitable container, and combinedwith a dessicant.

In yet an additional aspect, provided herein is a method of detectinglevels of 4-MMPPO in a composition comprising tolperisone. The methodcomprises the steps of (a) providing a composition comprisingtolperisone and optionally one or more excipients, (b) dissolving thecomposition in acidified alcohol to thereby prevent formation ofadditional 4-MMPPO, to form an acidified solution of tolperisone, (c)separating said tolperisone from the one or more excipients, if present,by extraction with an organic solvent to provide an acidified extract oftolperisone, (d) adding to the solution of (b) or (c) an internalstandard to quantify the amount of 4-MMPPO to provide a sample solution,and (e) analyzing the amount of 4-MMPPO in the sample solution by liquidchromatography/mass spectrometry, wherein at least one eluent employedin said liquid chromatography is acidified, to thereby detect levels of4-MMPPO in said sample that may be below 500 ppm.

In one embodiment of the foregoing method, the acidified alcohol isacidified with hydrochloric acid. In a particular embodiment, theacidified alcohol is methanolic hydrochloric acid.

In yet another embodiment of the method of detecting, the organicsolvent in (c) is an ether.

In yet another embodiment, the solvent is diisopropyl ether.

In yet another embodiment, the internal standard is deuterated MMPPO.

Additional embodiments of the present method, compositions, and the likewill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims, particularly when considered in conjunction with theaccompanying examples and drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a proposed chemical mechanism for formation of 4-MMPPO fromtolperisone via a β-elimination reaction.

FIG. 2 shows a proposed chemical mechanism for formation of 4-MMPPO viaa β-elimination of a γ-hydroxyketone side product of tolperisone.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey the scope of the invention to thoseskilled in the art.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

DEFINITIONS

It must be noted that, as used in this specification, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

The term, tolperisone, as well as reference to other chemical compoundsherein, is meant to include the compound in any of its pharmaceuticallyacceptable forms, including isomers such as diastereomers andenantiomers, salts, solvates, and polymorphs, particular crystallineforms, as well as racemic mixtures and pure isomers of the compoundsdescribed herein, where applicable.

“Pharmaceutically acceptable excipient or carrier” refers to anexcipient that may optionally be included in the compositions of theinvention and that causes no significant adverse toxicological effectsto the patient upon administration.

“Pharmaceutically acceptable salt” includes, but is not limited to,amino acid salts, salts prepared with inorganic acids, such as chloride,sulfate, phosphate, diphosphate, bromide, and nitrate salts, or saltsprepared from the corresponding inorganic acid form of any of thepreceding, e.g., hydrochloride, etc., or salts prepared with an organicacid, such as malate, maleate, fumarate, tartrate, succinate,ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate,ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, aswell as estolate, gluceptate and lactobionate salts. Similarly saltscontaining pharmaceutically acceptable cations include, but are notlimited to, sodium, potassium, calcium, aluminum, lithium, and ammonium(including substituted ammonium).

The term, “alkyl”, refers to a hydrocarbon chain, typically ranging fromabout 1 to 20 atoms in length. Such hydrocarbon chains are preferablybut not necessarily saturated and may be branched or straight chain,although typically straight chain is preferred. Exemplary alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, pentyl, 1-methylbutyl,1-ethylpropyl, 3-methylpentyl, and the like. As used herein, “alkyl”includes cycloalkyl when three or more carbon atoms are referenced.

“Lower” in reference to a particular functional group means a grouphaving from 1-6 carbon atoms.

For example, “lower alkyl” refers to an alkyl group containing from 1 to6 carbon atoms, and may be straight chain or branched, as exemplified bymethyl, ethyl, propyl, isopropyl, 1-ethylpropyl, 1,2-dimethylpropyl,n-butyl, i-butyl, sec-butyl, t-butyl, and the like.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

“Substantially absent” or “substantially free” of a certain feature orentity means nearly totally or completely absent the feature or entity.As used herein, a toloperisone formulation that is substantially absent4-MMPPO contains less than about 10 ppm 4-MMPPO.

A tolperisone composition that has been stored under “dry conditions” isone that has been stored under controlled humidity conditions (5-25percent relative humidity) and at temperatures ranging from about 18-25°C. The tolperisone composition may be the active pharmaceuticalingredient (API), or a pharmaceutical composition (powder or the like)comprising tolperisone and one or more pharmaceutically acceptableexcipients, or a finished product, for example, a capsule, tablet, etc.The composition is contained in a sealed container such as a bottle,blister, pouch, or a combination thereof. The composition may also bestored in the presence of a dessicant, such as silica, typically encasedin a pak suitable for absorption of water vapor.

“Anhydrous” refers to a material that is substantially absent water.

The terms “subject”, “individual” or “patient” are used interchangeablyherein and refer to a vertebrate, preferably a mammal. Mammals include,but are not limited to, humans.

The terms “pharmacologically effective amount” or “therapeuticallyeffective amount” of a tolperisone composition as provided herein, referto a non-toxic but sufficient amount of the composition or agent toprovide the desired response, e.g., improving symptoms related tospastic paralysis or for treating neuropathic pain and pain associatedwith various nervous system disorders has also been. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of the conditionbeing treated, additional drugs being taken by the subject, mode ofadministration, and the like. An appropriate “effective” amount in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation, based upon the information providedherein.

The term “about”, particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

Additional definitions may also be found in the sections which follow.

OVERVIEW

As described above, the present disclosure addresses the need to provideformulations of tolperisone in which the levels of 4-MMPPO aresignificantly and preferably consistently reduced over those found incommercial formulations, or those previously described. In preparing orobtaining and analyzing tolperisone compositions, in particular bydevising an extremely sensitive assay for detecting low levels of4-MMPPO, e.g., in tolperisone formulations, the inventors recognized theneed to provide formulations of tolperisone with improved purity,particularly with respect to the genotoxic agent, 4-MMPPO. As a result,formulations as described herein are administered to a subject fortreatment of a condition responsive to treatment with tolperisone, suchthat, as a result of such administering, genotoxic effects associatedwith the presence of 4-MMPPO in said tolperisone are minimized. Theseand other aspects of the invention will now be described in greaterdetail below.

FEATURES OF THE METHOD Toloperisone and Related Impurities

Tolperisone, also referred to as2-methyl-1-(4-methylphenyl)-3-(-piperidinyl)-1-propanone, possesses thechemical structure shown below.

Tolperisone contains a chiral center (as indicated by the asterisk inthe foregoing structure). Racemic tolperisone is commercially availableas the hydrochloride salt and is sold under trade names such asMydeton®, Mydocalm®, Midocalm® and Muscalm®. Reference herein totolperisone is meant to encompass racemic tolperisone, each of itsenantiomers, mixtures thereof in any proportion, as well aspharmaceutically acceptable salts, various crystalline forms, andhydrates thereof.

In addition to being obtained commercially, tolperisone can besynthesized by a variety of methods known in the art. See, e.g., U.S.Patent Application Publication No. 2006/0041141; Ditriech et al. (1999)J. Labeled Cpd. Radiopharm, 42:1125-1134; Jap. Pat. No. 0400528319920109; Jap. Pat. No. 54032480 19790309; Jap. Pat. No. 5403627419790316; Jap. Pat. No. 54030178 19790306; Jap. Pat. No. 5402757119790301; Kazuharu et al. (1994) Chem. Pharm. Bulletin 42(8) 1676; Jap.Pat. No. 20,390 (1965); and Hung. Pat. No. 144,997 (1956), eachincorporated herein by reference in its entirety.

Tolperisone may, for example, be prepared according to the followingsingle step synthesis scheme:

where 4-methylpropiophenone is used as the starting material. In theexemplary reaction above, 1,2-dioxolane acts as both reactant andsolvent. The use of 1,2-dioxolane in place of formaldehyde, and the highyield after direct isolation of the tolperisone crude product make thesingle-stage reaction particularly advantageous, e.g., due to itscost-effectiveness on an industrial scale, among other reasons. See,e.g., U.S. 2006/0041141.

In instances in which a particular enantiomer is desired, e.g., eitheror both of the R(−) and S(+) enantiomers, a chiral separation may becarried out, e.g., as described in JP-A-53-40779. Chiral separation mayalso be conducted as described in Velmurugan, et al., Chromatorgraphia,56 (3-4), August 2002, 229-232. Velmurugan describes reverse phase-HPLCseparation of tolperisone into each of its enantiomers.

Depending on the synthesis strategy employed, compositions oftolperisone may include any one or more of the following impurities:piperidine hydrochloride,2-methyl-1-(3-methylphenyl)-3-(1-piperidinyl)-propanone hydrochloride(3-tolperisone hydrochloride), 1-(4-methylphenyl)-propanone(4-methylpropiophenone), 2-methyl-1-(4-methylphenyl)-propenone(4-MMPPO), and 2-methyl-1-(2-methylphenyl)-3-(1-piperidinyl)-propanonehydrochloride (2-tolperisone hydrochloride). U.S. Patent Application No.US 2006/0041141 describes a synthesis method for significantly reducingthe content of the isomers, 2-tolperisone and 3-tolperisone, inpreparations of 4-tolperisone to form tolperisone having a final purifywith respect to these isomers that is substantially improved over priorformulations. However, to the inventors' knowledge, heretofore,formulations such as those described herein, that are substantiallyabsent 4-MMPPO, and/or stabilized against formation of the degradant,4-MMPPO, have not been provided, or have not been provided in areliable, consistent fashion. Nor has the significance of formulationssuch as those provided herein been previously recognized. The instantformulations are extremely advantageous for administration, since invivo exposure to 4-MMPPO in a subject undergoing treatment withtolperisone should be kept below stringent levels, due to the genotoxiceffects associated with 4-MMPPO.

Without being bound by theory, it is believed that the compound,4-MMPPO, is likely formed via a β-elimination reaction as demonstratedmechanistically in FIG. 1. Depending upon the synthesis conditions,4-MMPPO may also form via β-elimination of water from a potentialside-product, a γ-hydroxyketone, formed from an aldol-condensationreaction as shown in FIG. 2. The structure of 4-MMPPO is provided below.

Thus, 4-MMPPO may be formed as a side-product during the synthesis oftolperisone, or alternatively, may form during storage of tolperisone,when stored either solely (i.e., as active agent per se, commonlyreferred to as an “API” or “active pharmaceutical ingredient”), or aspart of a pharmaceutical formulation (i.e., in combination with one ormore pharmaceutically acceptable excipients). Additionally, 4-MMPPO mayform during the dissolution or heating phase of a recrystallizationprocedure employed to purify the API. Typically, most of any such4-MMPPO formed will remain in the mother liquor(s), although smallamounts may remained associated with the recrystallized tolperisone.After collection of the recrystallized tolperisone, a subsequent dryingstep may also facilitate formation of 4-MMPPO, particularly at elevatedtemperatures.

Analysis

In arriving at the tolperisone formulations provided herein, theinventors devised an optimized analytical method to detect extremely lowlevels of 4-MMPPO, where the method is capable of levels of detectionbelow about 0.05% weight (500 ppm) 4-MMPPO. Preferably, the method iscapable of detecting levels below about 400 ppm, or even below 300 ppm.Even more preferably, the method is capable of detecting levels of4-MMPPO below about 200, or even 100 ppm. It is believed that themethods provided herein are capable of detecting extremely low levels of4-MMPPO, e.g., less than about 50 ppm, or even less than 25 ppm, andmore preferably less than about 10 ppm 4-MMPPO. In the examples providedherein, levels less than about 9 ppm, less than about 8 ppm, less thanabout 7 ppm, less than about 6 ppm, less than about 5 ppm, less thanabout 4 ppm, less than about 3 ppm, less than about 2 ppm, less thanabout 1.5 ppm, or even less than 1 ppm are detectable. It is believedthat the present method is capable of detecting levels of 4-MMPPO downto about at least 0.5 ppm.

The method employed is based upon a combination of liquidchromatography-mass spectrometry (LC-MS). The present method overcomesthe disadvantages of prior methods unable to detect 4-MMPPO at levelsbelow about 500 ppm. Since 4-MMPPO is a genotoxic agent, its detectionto levels significantly below 500 ppm is extremely important, asproducers of tolperisone must be able not only to quantify the contentof potential genotoxins such as 4-MMPPO in pharmaceutical formulations,but must also be able to demonstrate that compositions containing evennegligible amounts of such genotoxins lack a genotoxic hazard whenadministered.

Generally, the method involves providing a composition of tolperisone.The tolperisone may be crude tolperisone formed during a syntheticreaction, purified tolperisone submitted to one or more purificationsteps, tolperisone obtained from a commercial source or a tollmanufacturer, or extracted from a pharmaceutical formulation such as atablet (e.g., Mydeton®, Mydocalm®, Midocalm® and Muscalm®) or otherdelivery form. For pharmaceutical formulations such as tablets, thesample is typically first homogenized with a suitable solvent to breakup the tablet formulation and provide a uniform solution or suspensionof the formulation components, thereby making extraction of tolperisone(and any associated 4-MMPPO) more facile. Suitable solvents forhomogenization include anhydrous isopropanol acidified with about 1% HClgas or about 1% anhydrous trifluoroacetic acid (TFA).

The tolperisone is dissolved in a suitable solvent system, such as anacidified alcohol. Illustrative solvents include methanol, isopropanol,butanol and other lower alcohols. Acids that may be employed to acidifythe solvent include, e.g. hydrochloric acid, hydrobromic acid, citricacid, formic acid, acetic acid, methanesulfonic acid, andtrifluoroacetic acid, among others. The inventors have recognized, intheir various attempts at analyses, that acidified conditions can beused to prevent additional base-catalyzed formation of 4-MMPPO, andstabilize the tolperisone during its analysis—thereby providing a moreaccurate reflection of the 4-MMPPO content in the sample. Preferably,the solvent(s) used to dissolve/suspend the sample is anhydrous, sincethe presence of even small amounts of water may lead to increasedformation of 4-MMPPO. One preferred acidified alcoholic solution ismethanolic HCl. The concentration of acid in the alcohol typicallyranges from about 10 mM to about 100 mM and is effective to stabilizethe tolperisone against further degradation to 4-MMPPO. In instances inwhich the tolperisone is part of a pharmaceutical formulation such as atablet, tolperisone may be extracted from any binders, fillers,excipients, and the like that may be contained in the formulation, e.g.,by extraction with an organic solvent. Solvents that may be employed arepreferably acidified alcoholic solvents such as those described above,although other solvents may be employed as well, such as ethers orlipophilic esters. Particular solvents that may be suitable includedichloromethane, chloroform, acetonitrile, amyl acetate, and dioxane.

Prior to analysis, an internal standard is typically added to thesample. In the present method, a preferred standard is deuterated4-MMPPO, such that the standard can be readily differentiated from4-MMPPO contained in the sample. The internal standard employed will ofcourse vary with the method of detection employed. Preferably, a bufferis added to the solution to be analyzed to maintain an acidic solution.Illustrative buffers include citrate, phosphate, and acetate.Preferably, the pH of the solution is below 5.5, and even morepreferably is below 4. Suitable pHs for the solution to be analyzed are5.5 or below, 5 or below, 4.5 or below, 4 or below, 3.5 or below, 3 orbelow, 2.5 or below, 2 or below, 1.5 or below, or 1.0 or below.

The sample is then analyzed for 4-MMPPO content. Although a number ofanalytical techniques can be employed for analysis, e.g., nuclearmagnetic resonance (NMR), gas chromatography (GC), mass spectrometry(MS), and combinations thereof, such as LC (liquid chromatorgraphy)/MS,GC/MS, GC/MS with negative chemical ionization, GC/MS/MS, MS/MS/LIT(linear ion trap), high performance liquid chromatography, HPLC/MS/MS,FT/IR (fourier transform infrared) and the like, a preferred method isliquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS), inparticular HPLC/MS/MS.

Different methods may be employed to obtain the mass spectra, includingtime-of-flight (TOF), quadrupole, ion trap, magnetic sector, andcombinations of the foregoing. Tandem quadrupole mass spectrometry(MS/MS) is preferred, due to its high signal-to-noise ratio (S/N). Themethod described herein, e.g., in Example 1, is capable of achieving alevel of detection of 4-MMPPO of below 500 ppm, to levels down to about0.2 ppm.

For analytical methods employing HPLC, solvents for use as eluentsinclude water, alcohols such as methanol, ethanol, isopropanol,acetonitrile, and combinations thereof. Preferably, at least one solventemployed as the mobile phase is acidified, to minimize formation ofadditional 4-MMPPO during the analysis. Suitable acids include formicacid, hydrochloric acid, phosphoric acid, trifluoroacetic acid, and thelike. HPLC columns can be obtained from a number of commercialsuppliers, such as PerkinElmer, EMScience, Phenomenex, and the like. Forinstance, columns such as those prepared by Shiseido, Shodex, Agilent(ZORBAX), and LUNA can be employed as the solid support. Normal orreversed phase columns can be used; preferred solid supports includesilica gel. Conditions for obtaining separation of components andquantification of contaminants such 4-MMPPO can be determined by one ofskill in the art.

Example 1 herein provides exemplary experimental conditions for analysisof tolperisone-containing formulations to determine 4-MMPPO content(Tables 1 and 2). The analytical method described herein allowsquantification of 4-MMPPO to levels undetectable by previous methods. Ascan be seen by the values provided in Table 3, values of 4-MMPPO invarious representative formulations (both API and commercialpharmaceutical formulations) were discovered to range from about 15 ppmto over 400 ppm. Commerical formulations Mydeton® and Mydocalm® allpossessed levels of 4-MMPPO that were in excess of 100 ppm. Due to thegenotoxic side effects associated with 4-MMPPO, the inventors recognizeda need to provide formulations having substantially lower levels of4-MMPPO than those detected for the formulations in Table 3, i.e., belowabout 10 ppm.

Purification

The inventors recognized a need to provide tolperisone compositions of agreater purity with respect to 4-MMPPO than have been previouslyprepared, preferably in a consistent manner. In this regard, variousapproaches were explored to achieve tolperisone formulations containingless than about 10 ppm 4-MMPPO. The methods described herein are capableof providing tolperisone with a level of 4-MMPPO that is less than about10 ppm. Tolperisone formulations as provided herein will thus containless than about 10 ppm 4-MMPPO, less than about 9 ppm, less than about 8ppm, less than about 7 ppm, less than about 6 ppm, less than about 5ppm, less than about 4 ppm, less than about 3 ppm, even less than about2 ppm. In a preferred embodiment, tolperisone as provided hereincontains from about 1.5 ppm to about 10 ppm 4-MMPPO.

Recrystallization—Single Stage

Typically an “impure” tolperisone composition for purification as setforth herein will contain greater than about 10 ppm 4-MMMPPO. One methodthat is particularly useful for removing trace amounts of 4-MMPPO isrecrystallization. Example 2 describes a conventional recrystallizationapproach for purifying tolperisone. As can be seen, dissolution oftolperisone in an organic solvent mixture (accomplished by heating toreflux), followed by hot filtration and cooling of the filtrate resultsin formation of crystalline tolperisone. Analysis of 4-MMPPO content inthe recrystallized product revealed about 0.14 percent by weighttolerpisone (1400 ppm), which was reduced in subsequent recrystallizedbatches to about 500 ppm or somewhat below. However, the level of4-MMPPO was unsuitable for pharmaceutical compositions of tolperisone.

However, single stage recrystallization may be suitable for providingtolperisone having the purity described herein when combined with one ormore additional approaches for minimizing or inhibiting formation of4-MMPPO as described in detail in the sections which follow.

Multiple Stage Recrystallization

Exploration of alternative recrystallization methods revealed thefollowing approaches for providing purified tolperisone that issubstantially absent of 4-MMPPO.

In one recrystallization approach, single stage recrystallization iscarried out. In certain instances, tolperisone having the desired puritymay be achieved in a single recrystallization. See, e.g., Example 3.

In another approach, multiple stage recrystallization is carried out.For example, tolperisone containing significant amounts of 4-MMPPO,i.e., greater than about 10 ppm, is submitted to multiplerecrystallizations, i.e., more than 1 recrystallization, preferably 2 ormore recrystallizations, to provide tolperisone that is substantiallyabsent 4-MMPPO. Typically, the number of recrystallizations is selectedfrom 2, 3, 4, 5, and 6. Ideally, the desired purity is achieved in 2, 3or 4 recrystallization steps. Solvents for use in recrystallizingtolperisione include single solvents as well as mixed solvent systems. Amixed solvent system may contain a combination of two solvents, threesolvents, four solvents, five solvents or more, but preferably willcontain two to four different solvents. Such solvents may optionally beacidified. Use of an acidified solvent may be effective in suppressingbeta elimination reactions, since such reactions are base-catalyzed.

Solvents for use in recrystallizing tolperisone include esters such asethyl acetate, methyl acetate, amyl acetate, ethers, preferably loweralkyl ethers such as diethyl ether, methyl tert-butyl ether (MTBE),ketones, preferably lower alkyl ketones such as 2-butanone, (methylethyl ketone, or MEK), methyl isobutyl ketone (MIBK), methyl propylketone, acetone, and the like, and alcohols. Preferred are loweralcohols such as methanol, ethanol, isopropanol, and the like. Mixturesof any of the foregoing may be employed. One preferred solvent systemcombines a lower ketone and a lower alcohol, e.g., methyl ethyl ketoneand isopropanol. Typically, tolperisone is first dissolved in one ormore recrystallization solvents. In certain instances, depending uponthe solvent(s) employed, heat may be used to aid in dissolution oftolperisone in the solvent system. Preferably, a solvent system isemployed in which tolperisone dissolves to an extent of about 100 mg/mlto about 200 mg/ml. Depending upon the boiling points of the solventsemployed, a solution of tolperisone may be heated to about 80° C., ifdesired. Agitation may also be employed to aid in dissolution. Theresulting solution is then typically allowed to cool, if heated, to roomtemperature or below. Ideally, cooling is done slowly, over a period ofminutes or one or more hours, up to several hours. In certain instances,an ice-bath may be employed to further cool the tolperisone solution.During crystal formation, the solution may optionally be stirred. A seedcrystal may also be added to induce crystal formation.

Crystals are collected and then washed with a suitable solvent, e.g.,one in which tolperisone is insoluble or only negligibly soluble. Onesolvent for use is 2-butanone, preferably cold 2-butanone.

The crystals are then dried. Preferred drying conditions are describedin the section below entitled, “Drying”. Drying will typically becarried out at either ambient temperatures or at slightly elevatedtemperatures, from about 30° C. to about 45° C., preferably from about30° C. to about 40° C.

The resulting purified tolperisone is then typically analyzed asdescribed above to determine 4-MMPPO content. For tolperisonecompositions possessing greater than about 10 ppm of 4-MMPPO, repeatedrecrystallizations are carried out as described above. See Example 3.

Acid Treatment

Due to the realization that 4-MMPPO formation can be suppressed in thepresence of acid, preferred methods of purification include treatment oftolperisone with acid. For example, recrystallized tolperisone may bewashed with an acidic solution, e.g., a solution containing from about10% (v/v) to about 0.5% acid, preferably from about 7% (v/v) to about 1%(v/v) acid. Inorganic acids such as hydrochloric acid, hydrobromic acid,and sulfuric acid may be used; organic acids such as formic acid, oxalicacid, acetic acid, citric acid, trifluoroacetic acid, toluenesulfonicacid, benzenesulfonic acid, naphthalenesulfonic acid, succinic acid, andthe like may also be employed. The acid solution may be an aqueoussolution of acid, or alternatively, may be an acidified solvent such asan acidified alcohol as long as the acidified solution is one in whichtolperisone is insoluble or only slightly soluble. One such exemplarysolvent system is HCl/isopropanol. See, e.g., Example 4. It has beendiscovered that treatment of tolperisone with acid (either duringsynthesis or post-synthesis) is effective to substantially lower thelevels of 4-MMPPO in the tolperisone product, such that tolperisone thatis substantially absent 4-MMPPO is obtained.

As an alternative to an acid wash, recrystallization as described abovemay be carried out using an acidified solvent/solvent system. Exemplaryrecrystallizations of tolperisone using an acidified solvent system areprovided in Examples 5 and 6. Single or multiple recrystallizations maybe employed. Preferably, an acid such as one or more of those describedabove is added to the recrystallization solvent/solvent system. Anamount of acid effective to acidify the solution while not destroying toany significant extent the active agent, tolperisone, is employed.Preferably, acid is added to the recrystallization solution to a totalweight/volume percent ranging from about 10 percent to about 0.5 percentacid, preferably from about 5 percent to about 1 percent (w/v).Illustrative amounts of acid include 5, 4, 3, 2, and 1% acid (w/v).Typically, the solvent system employed will contain about 1% (w/v) acid.Recrystallization under acidified conditions tends to prevent 4-MMPPOformation, and provide purified tolperisone that is substantially absent4-MMPPO.

In certain instances, where the tolperisone is either subjected to anacid wash or recrystallized from an acidified solvent, it may bepreferable to employ an acidified solvent that is dry—i.e., that issubstantially absent water. For example, dry HCl gas may be bubbled intoa solvent system where the solvent is essentially anhydrous, to providean acidified solvent system that is anhydrous or nearly so. Additionalacids include citric acid, trifluoroacetic acid, and succinic acid. Incertain studies, the inventors have observed increased levels of 4-MMPPOthat may be attributable to the presence of water—such that the use ofanhydrous conditions may be preferred.

Drying

In yet another approach to providing tolperisone that is substantiallyabsent 4-MMPPO, tolperisone, preferably tolperisone that has beenpurified as previously described, is dried over an extended period oftime ranging from one hour to several hours. Typical drying periods canextend from one hour to several hours, such as 72 hours or more. Dryingcan be carried out at room temperature and pressure, and may be carriedout over a dessicant such as phosphorous pentoxide. Drying may takeplace at elevated temperatures such as in a drying oven, preferably attemperatures from about 30° C. to about 40° C. Drying may also takeplace under reduced pressure (optionally accompanied by gentle heatingas described above), e.g., under low vacuum (e.g., from about 100,000 toabout 3,000 Pascal), medium vacuum (from about 3,000 to about 0.1Pascal) or even high vacuum (from about 0.1 to about 0.0001 Pascal). Thedrying process is effective to selectively remove 4-MMPPO fromtolperisone by evaporation (volatilization). Due to the difference involatility between tolperisone and 4-MMPPO, 4-MMPPPO can be selectivelyremoved from the composition. Removal of 4-MMPPO by volatilization cansimilarly be carried out using a vacuum oven, paddle drier, fluid beddrier, flash drier, tray drier, spray drier, or any other similar dryingtechnology, optionally at somewhat elevated temperatures, e.g., fromabout 30° C. to about 40° C.

As a result of the purification methodologies described above, incertain instances, depending upon the initial amount of 4-MMPPOcontained in the tolperisone, the amount of 4-MMPPO removed is reduceddramatically, i.e., by at least five-fold over its initial level. Forexample, in turning to Example 3, it can be seen that a composition oftolperisone containing an initial amount of 4-MMPPO of greater thanabout 500 ppm was purified to form a purified tolperisone containingfrom about 1.5 ppm to about 10 ppm 4-MMPPO—a reduction of from about 50times (50×) to about 300 (300×) times that of the original composition.Thus, depending upon the initial amount of 4-MMPPO, the purificationmethods provided herein can be effective to reduce the amount of 4-MMPPOby at least about 5-fold (or 5×), or at least about 10-fold, or at leastabout 20-fold, or at least about 30-fold, or at least about 50-fold, orat least 100-fold or more, in the resulting purified composition.

During Synthesis

Alternatively, rather than purify tolperisone post-synthesis asdescribed above, to remove 4-MMPPO, modified syntheses may be carriedout under certain modified reaction conditions. Such conditions includethe use of acidified and/or anhydrous reaction conditions.

For example, the synthesis of tolperisone as described above can becarried out in the presence of a catalytic amount of acid. Acidssuitable for such use include HCl (preferably gaseous), sulfuric acid,and nitric acid, formic acid, oxalic acid, acetic acid, citric acid, andthe like.

Anhydrous conditions can be favored by the use of dry solvents, such asthose obtained directly from a still and maintained over a drying agent,or solvents stored over molecular sieves or the like, and stored underan inert, dry atmosphere. Anhydrous reaction conditions can be furtherpromoted by carrying out the synthesis under a dry inert atmosphere,such as nitrogen or argon.

That is to say, tolperisone may be synthesized by any of the routesdescribed herein, or previously known, with the exception that, as animprovement, tolperisone is formed in the presence of a catalytic amountof acid and/or under anhydrous conditions.

Storage of Tolperisone

Example 7 provides data comparing the amount of 4-MMPPO contained in adrug lot used to make a tabletted pharmaceutical formulation, versus theamount of 4-MMPPO contained in the tablets after storage for a periodranging from 3 months to nearly 4 years. In nearly all of theformulations examined, a notable increase in the amount of 4-MMPPO wasobserved. While formation of 4-MMPPO may be attributable, at least inpart, to conditions under which the tablets were prepared, it also seemslikely that 4-MMPPO is formed in the pharmaceutical formulation over itsshelf life, i.e., upon storage. Regardless of the origination offormation of 4-MMPPO, pharmaceutical formulations of tolperisone foradministration to a subject should ideally contain significantly lowerlevels of 4-MMPPO than those in Example 7, and preferably, shouldcontain levels of 4-MMPPO that are less than about 10 ppm. Even morepreferably, a pharmaceutical formulation of tolperisone contains lessthan about 9 ppm, less than about 8 ppm, less than about 7 ppm, lessthan about 6 ppm, less than about 5 ppm, less than about 4 ppm, lessthan about 3 ppm, less than about 2 ppm, to about 1.5 ppm 4-MMPPO.

Preferably, tolperisone and tolperisone compositions as described hereinare stored under dry conditions. Dry conditions as used herein refers toa temperature ranging from about 18 to 23° C. and a relative humidity of5-25%. The subject formulation may be an API formulation, apharmaceutical composition comprising in addition to the API, one ormore pharmaceutically acceptable excipients, or a pharmaceuticalformulation for administration that is contained in a sealed containersuch as a bottle, blister pack, pouch, or a combination thereof. Thecomposition may also be stored in the presence of a dessicant, such assilica, typically encased in a pak suitable for absorption of watervapor.

Preferably, a tolperisone composition as provided herein comprisestolperisone in the form of an acid addition salt. In a preferredembodiment, a tolperisone composition as provided herein will alsocomprise an additional amount of an acidic additive or excipient toestablish an environment that is more acidic than that provided bytolperisone in the form of an acid addition salt. Such additives includeacetic acid, succinic acid, adipic acid, propionic acid, citric acid,toluenesulfonic acid, methanesulfonic acid, and the like. Preferredacids are di-acids or greater (e.g., di-acids, tri-acids, etc., havingmore than one acidic proton. Preferably, acids for use as stabilizersfor compositions of tolperisone will possess a pKa of less than about 3.Preferably, the acid is anhydrous. Particularly preferred acids includecitric acid and succinic acid.

Tolperisone may be combined within a glassy matrix; glass formers arewell known in the art, and may be effective in preventing chemicaldegradation of tolperisone to 4-MMPPO.

Ideally, tolperisone, irrespective of its formulation, is combined witha dessicant during storage, such that its exposure to moisture isminimized.

Genotoxicity of 4-MMPPO

4-MMPPO is considered genotoxic, that is, capable of causing geneticmutation and potentially contributing to the development of tumors.Genotoxicity is generally considered to be an intrinsic property ofcertain chemical agents. Based upon a compound's chemical structure, thecompound may possess sufficient electrophilicity to bind withnucleophilic sites in cellular macromolecules such as DNA.

Ideally, tolperisone compositions provided herein, when evaluated ingenetic toxicology studies, indicate a lack of genotoxic potential—dueat least in part to the extremely low levels of 4-MMPPO containedtherein. Genetic toxicology studies suitable to assessing genotoxichazard include the following rodent in vitro assays: a test for genemutation in bacteria 3B, an in vitro assessment of chromosomal damageusing mammalian cells or an in vitro mouse lymphoma tk^(+/−) assay, andan in vivo test for chromosomal damage using rodent hematopoietic cells.Alternative models for assessing carcinogenicity can be found in ICHguidance for industry S1B Testing for Carcinogenicity ofPharmaceuticals.

In vivo assays may also be used to further indicate a lack of genotoxicpotential, especially in instances in which results from an in vitrostudy may suggest a potential genotoxic hazard. In vivo assays that maybe employed to indicate a lack of genotoxicity of the tolperisonecompostions provided herein include the following. For example,peripheral blood smears from repeat dose toxicity studies in mice may beevaluated for micronucleus induction. Peripheral blood lymphocytes fromrepeat dose studies in rats or monkeys can be cultured and assessed forchromosome damage in metaphase spreads. Additionally, DNA damage (e.g.,(DNA adducts or DNA strand breakage using the Comet or alkaline elutionassay) can be assessed in potential target tissues. Transgenic rats ormice can also be used to assess mutagenicity in potential targettissues.

The Syrian hamster embryo cell (SHE) transformation assay may also beused. Further, transgenic mouse strains such as the p53 haploinsufficient mouse may be used in short-term carcinogenicity studies.

A substantial absence of genotoxic side effects (or genotoxicity) of aformulation as provided herein, in reference to a tolperisonecomposition comprising less than about 10 ppm 4-MMPPO when administeredto a subject at a pharmaceutically acceptable dose, is indicated basedupon a negative result in at least one of the three in-vitro studiesdescribed above. Preferably, at least two of the in-vitro assays arenegative, and even more preferably, all three of the in-vitro assays arenegative with respect to genotoxicity. In instances in which one or moreof the in-vitro studies described above provides a positive or less thanconclusive result in terms of lack of genotoxicity, a negative result inone or more of the above-described in-vivo studies may be relied upon todemonstrate a lack of genotoxicity.

Pharmaceutical Formulation Components

In addition to comprising tolperisone, a formulation of the inventionmay optionally contain one or more additional components.

A composition of the invention may comprise, in addition to tolperisone,one or more pharmaceutically acceptable excipients or carriers.Exemplary excipients include, without limitation, polyethylene glycol(PEG), hydrogenated castor oil (HCO), cremophors (polyethoxylated castoroil), carbohydrates, starches (e.g., corn starch), inorganic salts,antimicrobial agents, antioxidants, binders/fillers, surfactants,lubricants (e.g., calcium or magnesium stearate), glidants such as talc,disintegrants, diluents, buffers, acids, bases, film coats, combinationsthereof, and the like.

A composition of the invention may include one or more carbohydratessuch as a sugar, a derivatized sugar such as an alditol, aldonic acid,an esterified sugar, and/or a sugar polymer. Specific carbohydrateexcipients include, for example: monosaccharides, such as fructose,maltose, galactose, glucose, D-mannose, sorbose, and the like;disaccharides, such as lactose, sucrose, trehalose, cellobiose, and thelike; polysaccharides, such as raffinose, melezitose, maltodextrins,dextrans, starches, and the like; and alditols, such as mannitol,xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, myoinositol, and the like.

Also suitable for use in the compositions of the invention are potatoand corn-based starches such as sodium starch glycolate and directlycompressible modified starch.

Further representative excipients include inorganic salts or bufferssuch as citric acid, sodium chloride, potassium chloride, sodiumsulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphatedibasic, and combinations thereof.

A tolperisone composition may also include an antimicrobial agent, e.g.,for preventing or deterring microbial growth. Non-limiting examples ofantimicrobial agents suitable for the present invention includebenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate, thimersol, and combinations thereof.

A composition as provided herein may also contain one or moreantioxidants. Antioxidants are used to prevent oxidation, therebypreventing the deterioration of the tolperisone or other components ofthe preparation. Suitable antioxidants for use in the present inventioninclude, for example, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propylgallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite, and combinations thereof.

Additional excipients include surfactants such as polysorbates, e.g.,“Tween 20” and “Tween 80,” and pluronics such as F68 and F88 (both ofwhich are available from BASF, Mount Olive, N.J.), sorbitan esters,lipids (e.g., phospholipids such as lecithin and otherphosphatidylcholines, and phosphatidylethanolamines), fatty acids andfatty esters, steroids such as cholesterol, and chelating agents, suchas EDTA, zinc and other such suitable cations.

Further, as described previously, a composition of the invention mayoptionally include one or more acids. Non-limiting examples of acidsthat can be used include those acids selected from the group consistingof hydrochloric acid, acetic acid, phosphoric acid, citric acid,succinic acid, adipic acid, propionic acid, toluenesulfonic acid,methanesulfonic acid, malic acid, lactic acid, formic acid,trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid,sulfuric acid, fumaric acid, and combinations thereof.

In a preferred embodiment, a composition as provided herein is absent abasic component.

The amount of any individual excipient in the composition will varydepending on the role of the excipient, the dosage requirements of theactive agent (i.e., tolperisone), and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thendetermining the range at which optimal performance is attained with nosignificant adverse effects.

Generally, however, the excipient will be present in the composition inan amount of about 1% to about 99% by weight, preferably from about 5%to about 98% by weight, more preferably from about 15 to about 95% byweight of the excipient. In general, the amount of excipient present ina tolperisone composition of the invention is selected from thefollowing: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

Exemplary formulations for administration are those currently on themarket, e.g., Mydeton®, Mydocalm®, Midocalm® and Muscalm®, and similarsuch formulations. A formulation for oral administration may, forexample, contain from about 50 to about 750 mg of tolperisone,preferably from about 100 to about 500 mg of tolperisone. For example,formulations for oral administration may, in certain instances, containany one of the following amounts of tolerperisone: 100 mg, 150 mg, 200mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of tolperisone.

Tolperisone may be provided in a sustained-release formulation. See,e.g., Example 9, and International Patent Publication No. WO2005/094825. Controlled or sustained-release formulations are typicallyprepared by incorporating tolperisone into a carrier or vehicle such asliposomes, nonresorbable impermeable polymers such as ethylenevinylacetate copolymers and Hytrel® copolymers, swellable polymers such ashydrogels, or resorbable polymers such as collagen and certain polyacidsor polyesters such as those used to make resorbable sutures.

One exemplary controlled release formulation includes a mixture ofanionic and cationic polymers, such as Eudragit RS, Eudragit L andEudragit S. Additionally, tolperisone can be encapsulated, adsorbed to,or associated with, particulate carriers. Examples of particulatecarriers include those derived from polymethyl methacrylate polymers, aswell as microparticles derived from poly(lactides) andpoly(lactide-co-glycolides), known as PLG. See, e.g., Jeffery et al.,Pharm. Res. (1993) 10:362-368; and McGee et al., J. Microencap. (1996).Tablets or caplets may also be coated with water insoluble polymers,e.g, Aquacoat® and Eudragit®.

The foregoing pharmaceutical excipients along with other excipients aredescribed in “Remington: The Science & Practice of Pharmacy”, 19^(th)ed., Williams & Williams, (1995), the “Physician's Desk Reference”,52^(nd) ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H.,Handbook of Pharmaceutical Excipients, 3^(rd) Edition, AmericanPharmaceutical Association, Washington, D.C., 2000.

Pharmaceutical Formulations/Delivery Forms

The tolperisone described herein may be formulated into any formsuitable for administration. Oral dosage forms include tablets,lozenges, capsules, syrups, oral suspensions, emulsions, granules, andpellets. Alternative formulations include aerosols, transdermal patches,gels, creams, ointments, suppositories, powders or lyophilates that canbe reconstituted, as well as liquids. With respect to liquidpharmaceutical compositions, solutions and suspensions are envisioned.Preferably, tolperisone is provided in a form suitable for oraladministration.

For example, tablets can be made by compression or molding, optionallywith one or more accessory ingredients or additives. Compressed tabletsare prepared, for example, by compressing in a suitable tablettingmachine, the active ingredients in a free-flowing form such as a powderor granules, optionally mixed with a binder (e.g., povidone, gelatin,hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (e.g., sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose) and/or surface-active ordispersing agent.

Molded tablets are made, for example, by molding in a suitabletabletting machine, a mixture of powdered compounds moistened with aninert liquid diluent. The tablets may optionally be coated or scored,and may be formulated so as to provide slow or controlled release of theactive ingredients, using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile. Tablets mayoptionally be provided with a coating, such as a thin film, sugarcoating, or an enteric coating to provide release in parts of the gutother than the stomach. Processes, equipment, and toll manufacturers fortablet and capsule making are well-known in the art.

The compositions of the present invention may also be prepared in a formsuitable for veterinary applications.

Administration

Methods of administering therapeutic formulations of tolperisone includebut are not limited to oral, intra-arterial, intrathecal, intraspinal,intramuscular, intraperitoneal, intravenous, intranasal, and inhalationroutes. Preferred routes of administration are intramuscular,intravenous, and oral. In a particularly preferred embodiment,tolperisone is administered orally. However, tolperisone may beadministered by any suitable route, including without limitation, oral,rectal, nasal, topical (including transdermal, aerosol, buccal andsublingual), vaginal, parenteral (including subcutaneous, intramuscular,intravenous and intradermal), intrathecal, and pulmonary. The preferredroute will, of course, vary with the condition and age of the recipient,the particular condition being treated, and the specific combination ofdrugs employed, if any.

Provided herein is a method of treating a subject with tolperisone underconditions that minimize exposure to 4-MMPPO. In certain embodiments,exposure to 4-MMPPO is minimized by administering a tolperisonecomposition of the invention containing 4-MMPPO in an amount of lessthan 10 ppm, and preferably, less than about 7 ppm. Such compositionscan be prepared by any of the methods described herein. In preferredembodiments, the subject is treated with a tolperisone compositioncontaining from about 10 ppm to about 1.5 ppm 4-MMPPO.

Treatment

Tolperisone is a centrally-acting muscle relaxant that acts on thecentral nervous system and is used mainly for the treatment of elevatedmuscle tone and tension, as well as for certain circulatory problems inthe extremities. Tolperisone has been found to reduce experimentalhypertonia and decerabration rigidity, as well as inhibit reticulospinalreflex facilitation without affecting cortical functions. It alsoimproves peripheral blood flow (Toperin® Package Insert).

Tolperisone is useful in treating a number of conditions. For example,tolperisone may be administered to a subject suffering from one of moreof the following conditions including: muscle spasm, spastic syndromes,muscle soreness, myotonia, dysmenorrhea, climacteric complaints,lockjaw, neurolatyrism, osteoarthritis or rheumatoid arthritis (whenadministered in combination with a non-steroidal anti-inflammatorydrug), rheumatic diseases, fibromyalgia syndrome, occupational andsport-related stress, back pain, spasticity caused by neurologicaldiseases, multiple sclerosis, myelopathy, encephalomyelitis, stroke,muscular hypertension, muscular contracture, spinal automatism,obliterative vascular diseases (e.g., obliterative arteriosclerosis,diabetic angiopathy, obliterative thromboangitis, Raynaud's disease,diffuse scleroderma), disorders due to injured innervation of thevessels (acrocyanosis, intermittent angioneurotic dysbasis), neuropathicpain, and in individual cases, post-thrombotic venous and lymphaticcirculation disorders, diabetic neuropathy, post-herpetic neuralgia, andcrural ulcer (Myolax® Package insert).

Subjects to whom tolperisone may be administered include both children(aged three months to 18 years), and adults (18 years and older).

Dosage

A therapeutic amount of tolperisone can be empirically determined andwill vary with the particular condition being treated, the subject, andthe like. The actual dose to be administered will vary depending uponthe age, weight, and general condition of the subject as well as theseverity of the condition being treated, the judgment of the health careprofessional, and particular dosage form being administered.

A therapeutically effective amount of tolperisone can be determined bythose skilled in the art, and will be adjusted to the requirements ofeach particular case. Generally, a therapeutically effective amount oftolperisone for an adult will range from a total daily dosage of betweenabout 10 and 3000 mg/day, preferably, in an amount between 25-2000mg/day, more preferably, in an amount between about 50-1800 mg/day.Typical dosage ranges for adults include total daily dosage ranges fromabout 150-1000 mg/day, preferably from about 150 to about 750 mg/day,administered as either a single dosage or as multiple dosages. Preferredin certain embodiments are divided dosages over the course of a day,e.g., a recommended daily dose divided into five doses, or four doses,or three doses, or two doses. Preferred dosage amounts include dosagesfrom about 50 mg to 450 mg twice daily or three times daily. That is tosay, dosage amounts may be selected from 50 mg/day, 100 mg/day, 150mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450mg/day, 500 mg/day or more.

Depending upon the dosage amount and precise condition to be treated,administration can be one, two, or three times daily for a time courseof one day to several days, weeks, months, and even years, and may evenbe for the life of the patient. Illustrative dosing regimes will last aperiod of at least about a day, a week, from about 1-4 weeks, from 1-3months, from 1-6 months, from 1-50 weeks, from 1-12 months, or longer.Dosage amounts for children ranging in age from 3 months to 18 years inage range from about 1-25 mg/kg/day, preferably from about 2-15 mg/day,in from about 2-4 divided doses, preferably 3 doses. Exemplaryrecommended dosage ranges for children include 5-10 mg/kg/day and from2-4 mg/kg/day, in 2-3 divided doses.

Practically speaking, a unit dose of any given composition of theinvention or active agent can be administered in a variety of dosingschedules, depending on the judgment of the clinician, needs of thepatient, and so forth. The specific dosing schedule will be known bythose of ordinary skill in the art or can be determined experimentallyusing routine methods.

Additionally, the dosage of a tolperisone composition administered to asubject can be limited to prevent overexposure of the subject to4-MMPPO. In a preferred embodiment, less than 45 μg of 4-MMPPO per doseof tolperisone is administered to the subject, and less than 135 μg of4-MMPPO is administered to the subject per day. The duration oftreatment of a subject with tolperisone can also be kept relativelyshort (2 weeks or less) in order to keep 4-MMPPO levels within tolerablelimits for the subject.

EXAMPLES

The following examples illustrate certain aspects and advantages of thepresent invention, however, the present invention is in no wayconsidered to be limited to the particular embodiments described below.

The practice of the invention will employ, unless otherwise indicated,techniques of pharmaceutical formulation, separations, pharmacology, andthe like, which are within the skill of the art, based upon the guidanceprovided herein. See, for example, Handbook of PharmaceuticalManufacturing Formulations, S. K. Niazi (ed.), CRC Press, 2004; Goodman& Gilman, The Pharmacological Basis of Therapeutics, 9^(th) Edition,Hardman, J. G., Gilman, A. G., Limbird, L. E. (eds.), McGraw-Hill, NewYork, 1995; Basic and Clinical Pharmacology, 18^(th) Edition, Katzung,B. G. (ed.), Appleton & Lange, Norwalk, C N, 2001.

In the following examples, efforts have been made to ensure accuracywith respect to numbers used (e.g., amounts, temperatures, etc.) butsome experimental error and deviation should be accounted for. Each ofthe following examples is considered to be instructive to one ofordinary skill in the art for carrying out one or more of theembodiments described herein.

Example 1 Analysis of Commercial Tolperisone Compositions for 4-MMPPOContent

Tolperisone compositions were obtained from various commercial sourcesand analyzed for 4-MMPPO content by HPLC-MS/MS.

All samples used in the analytical sequence were prepared for analysisas follows. Sample were homogenized if necessary (e.g., tablets) andweighed. For each tolperisone sample, approximately 20 mg of sample wasadded into a 20 mL flask. 20 mL of 50 mM HCl in MeOH was added to theflask, which was then placed in an ultrasonic bath for about 5 minutes.The contents of the flask were mixed on a vortexer for about 20 seconds.In instances in which the tolperisone sample had initially been intablet form, the solution was then centrifuged at 4000 rpm for 2minutes. 200 μL of the sample was then transferred into a small conicalcentrifuge vial. 20 μL of an internal standard solution containingdeuterated 4-MMPPO, 200 μL of buffer at pH 1, and 0.4 mL of diisopropylether (DIPE) were added to the vial. The sample was then extracted byvortexing with a DVX-2500 multi-tube vortexer (2100 rpm) for about 2minutes (cycle: 5 seconds run, 1 second pause time) and centrifugation(phase separation) at 4000 rpm for 2 minutes. 150 μL of 50 mM HCl inMeOH/DMSO (½) was added into empty designated conical autosampler vials.After centrifugation, 100 μL of supernatant was transferred into theseconical autosampler vials. The vials were crimped and vortexed with aDVX-2500 multi-tube vortexer (2100 rpm) for about 1 minute. 7 μL of theprepared sample was then injected immediately into an HPLC-MS/MS systemor the sample was stored at a temperature below −20° C. until analysis.The chromatography conditions and mass spectrometry parameters used foranalysis of 4-MMPPO are shown below in Tables 1 and 2, respectively.

TABLE 1 CHROMATOGRAPHIC CONDITIONS FOR ANALYSIS OF 4-MMPPO Mobile phasesolvent A 50 mM formic acid in water Mobile phase solvent B 50 mM formicacid in MeOH Gradient 0.0 min: switching LC to waste, external (50%methanol) to MS 0.0-0.8 min linear: 45% B → 67% B 0.8-1.7 min linear:67% B → 88% B (LC to MS) 1.7-2.4 min isocratic: 45% B (LC to waste) Flow1 mL/min Column LUNA ® HPLC column (Phenomenex, Germany); C₁₈ bondedsilica gel 5 μm, C18(2), 2 × 50 mm Column temperature 50° C. Retentiontime approximately 1.3 min: 4-MMPPO and D7-4- MMPPO Injection volume 7μL

TABLE 2 MS-DETECTION OF 4-MMPPO Atmospheric pressure chemical ionizationinterface (APCI) MS detection in positive ion mode Vaporizer temperature450° C. Corona needle current 5 μA Gas 1 pressure = 60 psi Curtain gaspressure = 45 psi Lateral position approximately 5 units (default)Vertical position approximately 10 units Quadrupole resolution unit →unit Detection mode MRM Transitions 161.1 → 143.1 m/z: 4-MMPPO 161.1 →128.1 m/z: 4-MMPPO-qual 168.1 → 150.1 m/z: D7-4-MMPPO 168.1 → 132.1 m/z:D7-4-MMPPO

TABLE 3 4-MMPPO CONTENT IN COMMERCIALLY AVAILABLE TOLPERISONEFORMULATIONS Time from Manuf. Sample Date to [4-MMPPO], No.Manufacturer* Lot No. Dosage Manuf. Date Analysis ppm 1 A 204406 150 mgAugust 2006 6 68 2 A 204506 150 mg August 2006 6 56 3 A 206506 150 mgAugust 2006 6 51 4 A 257506 100 mg November 2006 3 40 5 A 167106 150 mgJune 2006 8 100 6 B 243806 150 mg October 2006 4 15 7 B 247106 150 mgSeptember 2006 5 14 8 B 247206 150 mg September 2006 5 19 9 B 307003 150mg July 2003 43 22 10 C T66612A  50 mg June 2006 8 215 11 C T6A207A 150mg October 2006 4 107 12 D 506223  50 mg May 2005 21 442 *A = Merck; B =Viatris (now part of Meda AB, Sweden); C = Mydeton ®, D = Mydocalm ®

As a result of the analytical 4-MMPPO assay developed by the inventorsand its sensitivity to extremely low levels of detection, the data inthe table above revealed significant amounts of 4-MMPPO in each sampleexamined, and certainly in excess of the levels contained in thepurified tolperisone formulations described herein and in the exampleswhich follow. Most notable are samples 1, 2, 3, 5 and 10, 11, 12, eachof which contain surprisingly high levels of 4-MMPPO, i.e., greater than50 ppm 4-MMPPO. Due to the association of 4-MMPPO with genotoxicity, theinventors recognized an immediate need to arrive at formulations oftolperisone having levels of 4-MMPPO that are significantly lower thancurrent commercial formulations such as those above.

Upon recognizing this shortcoming with currently available formulationsof tolperisone, the inventors explored and arrived at various approachesto providing pure compositions of tolperisone having levels of 4-MMPPOthat are significantly reduced from those levels found in prior artformulations, such as those described above and also described in U.S.Patent Application No. 2006/0041141. The formulations provided hereinpossess the advantage of possessing 4-MMPPO-associated genotoxic sideeffects that are significantly reduced over the prior art formulations(such as those represented by the illustrative sampling above), byvirtue of their lowered (i.e., minimal) levels of 4-MMPPO).

Example 2 Standard Recrystallization of Tolperisone

Tolperisone samples identified during production as containing 4-MMPPOat levels of greater than 0.5% by weight were employed as startingmaterial (referred to as ‘crude’). Crude tolperisone was dissolved in an85:15 (v/v) mixture of 2-butanone (methyl ethyl ketone) and isopropanolunder reflux for 30 minutes. The resulting solution was cooled to 80°C., and the solution was filtered while hot. The filtered solution wasthen cooled to 5° C., and stirred for an additional 7 hours. Theresulting crystalline precipitate was separated by filtering, followedby washing with methyl ethyl ketone. The recrystallized material wasdried in vacuo at 45-85° C.

Based upon HPLC-MS/MS analysis, the recrystallized tolperisone possessed0.14% by weight 4-MMPPO; in subsequent production batches, 4-MMPPO wasdetected to be less than but around 0.05% (500 ppm), but nowhere nearthe desired level of 10 ppm or below. This may have been due to theamount of tolperisone contained in the starting material, such that theamount was greater than could be substantially removed in a singlerecrystallization, or due to the presence of residual methyl ethylketone in the recrystallized product, which upon heating to dry theproduct facilitated formation of 4-MMPPO, or a combination thereof.

The resultant recrystallized tolperisone possessed levels of 4-MMPPOwhich were considered unsatisfactory for administration to a subject,due to the potential for associated genotoxic side effects related tothe level of 4-MMPPO.

Example 3 Multiple Stage Recrystallization of Tolperisone

The approach utilized in Example 2 above was repeated with the exceptionthat multiple stage (repeated) recrystallizations were carried out.

TABLE 4 4-MMPPO Content Following Repeated Recrystallizations,Non-Acifidified Solvent [4-MMPPO], [4-MMPPO], [4-MMPPO], [4-MMPPO], ppmppm ppm ppm Crude After 1st After 2nd After 3rd Batch TolperisoneRecryst. Recryst. Recryst. 1 107/51.1 <6.6 8.3 <6.6 before/after drying2 7/<6.6 7.3 6.2 —As can be seen from the results in Table 4, multiple recrystallizationsfrom solvents/solvent systems such as methyl ethyl ketone andisopropanol can be effective to provide tolperisone that issubstantially absent 4-MMPPO.

Example 4 Recrystallization of Tolperisone Followed by Acid Wash

Crude tolperisone having a 4-MMPPO content of greater than 0.05% byweight was dissolved in an 85:15 mixture of 2-butanone (MEK) andisopropanol under reflux for 12 hours. The temperature was decreased to80° C. and the solution filtered while hot. The filtered solution wascooled to 5° C. and stirred for 7 h at 5° C.

The crystalline precipitate was separated by filtering and washed with a1% HCl/isopropanol mixture, and subsequently dried in vacuo at 45 to 85°C.

Based upon the recognition of potential side reactions of tolperisone asdemonstrated in FIGS. 1 and 2, the inventors realized the benefit of anabsence of base in minimizing the occurrence of β-elimination of eithertolperisone or its corresponding α-hydroxy ketone side product to form4-MMPPO, and the value of recrstallization and/or washing the product inthe presence of acid.

Based upon HPLC-MS/MS analysis, a content of 4-MMPPO in the range of 1.5to 10 ppm was detected in the recrystallized product, revealing asurprising and significant improvement over currently availablecommercial formulations of tolperisone.

Example 5 Recrystallization of Tolperisone Using Acidified SolventSystem

Crude tolperisone was dissolved in an 85:15 (v/v) mixture of 2-butanone(MEK) and isopropanol, accompanied by addition of 1% HCl under refluxfor 12 hours. The temperature was decreased to 80° C. and the solutionfiltered while hot. The solution was cooled to 5° C. and stirred for 7 hat 5° C.

The crystalline precipitate was separated by filtering, washed withisopropanol, and subsequently dried in vacuo at 45 to 85° C., with lowerdrying temperatures being preferred.

Tolperisone showed enhanced stability during recrystallization in thepresence of acid. When 1% (v/v) concentrated aqueous HCl was added tothe recrystallization mixture, 4-MMPPO levels dropped below 6.6 ppm inthe final recrystallized tolperisone product.

Example 6 Multiple Recrystallizations of Tolperisone Using AcidifiedSolvent System

Crude tolperisone (Lot SPH-3047, Batches 1 and 2) was dissolved in an85:15 (v/v) mixture of 2-butanone (MEK) and isopropanol, accompanied byaddition of 1% HCl, under reflux for 12 hours. The temperature wasdecreased to 80° C. and the solution filtered while hot. The solutionwas cooled to 5° C. and stirred for 7 h at 5° C.

The crystalline precipitate was separated by filtering, washed withisopropanol, and subsequently dried in vacuo at 45 to 85° C., with lowertemperatures being preferred.

The above recrystallization process was repeated 4 times.

TABLE 5 4-MMPPO Content Following Repeated Recrystallizations UsingAcidified Solvent [4- [4- [4- [4- [4- MMPPO], MMPPO], MMPPO], MMPPO],MMPPO], ppm ppm ppm ppm ppm Crude After 1st After 2nd After 3rd After3rd Batch Tolperisone Recryst. Recryst. Recryst. Recryst. 1 107/51.1<6.6 <6.6 <6.6 <6.6 Before/after drying 2 7/<6.6 <6.6 <6.6 <6.6 <6.6

While the first recrystallization under acidified conditions exhibitedthe most significant removal of 4-MMPPO and purification of tolperisone,additional recrystallizations were also effective in further reducingthe content of 4-MMPPO in the final drug product.

Example 7 Investigation of 4-MMPPO Levels in Tolperisone Drug LotsVersus Manufactured Tablets

TABLE 6 MS-DETECTION OF 4-MMPPO IN DRUG LOTS AND IN TABLETTEDFORMULATIONS [4- Time from [4- MMPPO Manuf. MMPPO Manu- Drug in DrugDate to in Lot No. fac- Lot in Lot or Analysis Tablet], Tablet turerTablet API], ppm (mos) ppm 257506/040 A SFO192 21 3 39 204406 A SD0108,14 6 66 SE0107 20 204506 A SF0093 — 6 56 206506 A SF0094 — 6 51 SF0096167106 A SD0108 14, 20 8 99 SE0107 243806 B SF0191 22, 21 4 14 SF0192247206 B SF0097 — 4 18 247106 B SF0095 — 5 13 307003 B SB0068 39 43 21*A = Merck; B = Viatris (now part of Meda AB, Sweden);

Lots of tolperisone were obtained from manufacturers A and B, as werethe final manufactured tablet formulations. Analyses were carried out asdescribed in Example 1 to determine 4-MMPPO levels in both drug lots andfinal manufactured formulations. As can be seen from an examination ofTable 5 above, in nearly 90% of the cases, a notable increase in thelevel of 4 MMPPO was observed when comparing drug lots (API,manufactured drug per se, i.e., absent additives, stabilizers,excipients, etc.) with final pharmaceutical formulations (in this case,tablets).

As a result of this study, the inventors recognized the problem of4-MMPPO not only present in drug lots, but also in final pharmaceuticalformulations. Based upon the results in the table above, it appears that4-MMPPO is formed not only during preparation of tolperisone (API),and/or during its purification, and/or during formulation (e.g.,blending), but also forms as a degradant during the shelf life (i.e.,upon storage) of the final pharmaceutical formulation. Thus, based uponthis data, the inventors further recognized the advantage of minimizingformation of 4-MMPPO not only during preparation of tolperisone, or inthe purified drug product per se, but also in the final pharmaceuticalformulation over its shelf life.

Example 8 Instant Release Caplet Formulation

A solution of anhydrous citric acid, 2-butanone and isopropyl alcohol isprepared. Tolperisone hydrochloride containing less than 10 ppm 4-MMPPOis transferred into a granulator, into which the already preparedsolution is placed. This mixture is homogenized and subsequently driedin a drier at 60° C., or more preferably, at 40° C. The formed granulateis sifted through a 1.8 mm screen. Silicon dioxide and talcum are addedand likewise mixed. Subsequently, the mixture is further mixed withmagnesium stearate.

Tablets having a diameter of 8 mm and a weight of 155.8-172.2 g areproduced. The finished granulate is coated with a suspension ofhypromellose/hypromellose phthalate in ethanol/water, dyes and additivesin a coating tank at a temperature of 55-60° C. The coated tablets aresubsequently dried at room temperature.

Example 9 Controlled Release Formulation

Tolperisone containing less than 10 ppm 4-MMPPO as described herein isgranulated as the hydrochloride salt in a mixer with a solutionconsisting of Eudragit RS in butanone with addition of anhydrous citricacid. Subsequently, Eudragit S and Eudragit L are incorporatedhomogeneously; the mixture is dried and sifted. To the sifted granulateare added tabletting auxiliary agents, and the granulate is tabletted.Tablets having a diameter of 8 mm and a weight of 190 mg are pressed.

Subsequently, the tablets are coated (“filmed”) with a film materialconsisting of Eudragit L, dyes, and miscellaneous auxiliary agents,which are dissolved in butanol.

TABLE 7 Ingredient Grams Tolperisone hydrochloride 150.00 Eudragit RS1.88 Eudragit L 14.24 Eudragit S 10.50 Aerosil 1.80 Stearic acid 1.80Glycerol dibehenate 7.50 Iron oxide dye 0.08 Titanium dioxide 4.08Talcum 6.03 Polyethylene glycol 1.02 Dimethylpolysiloxane 0.05

What is claimed is:
 1. A method of relaxing a muscle in a subject,comprising: a. administering to a subject in need thereof atherapeutically effective amount of a pharmaceutically acceptable acidaddition salt of tolperisone, or hydrate thereof, comprising 5 ppm2-methyl-1-(4-methylphenyl)-propenone (4-MMPO) or less.
 2. The methodaccording to claim 1, wherein the pharmaceutically acceptable acidaddition salt of tolperisone, or hydrate thereof, comprises 4 ppm4-MMPPO or less.
 3. The method according to claim 1, wherein thepharmaceutically acceptable acid addition salt of tolperisone, orhydrate thereof, comprises 3 ppm 4-MMPPO or less.
 4. The methodaccording to claim 1, wherein the pharmaceutically acceptable acidaddition salt of tolperisone, or hydrate thereof, comprises 2 ppm4-MMPPO or less.
 5. The method according to claim 1, wherein thepharmaceutically acceptable acid addition salt of tolperisone comprisestolperisone hydrochloride.
 6. The method according to claim 1, whereinthe pharmaceutically acceptable acid addition salt of tolperisone, orhydrate thereof, is formulated as a pharmaceutical compositioncomprising one or more excipients.
 7. The method according to claim 1,wherein the therapeutically effective amount of a pharmaceuticallyacceptable acid addition salt of tolperisone, or hydrate thereof, isbetween about 10 mg/day and 3,000 mg/day.
 8. The method according toclaim 1, wherein the therapeutically effective amount of apharmaceutically acceptable acid addition salt of tolperisone, orhydrate thereof, is between about 150 mg/day and 1,000 mg/day.
 9. Themethod according to claim 1, wherein administering occurs by an oral,intra-arterial, intrathecal, intraspinal, intramuscular,intraperitoneal, intravenous, intradermal, intranasal, inhalation,rectal, nasal, topical, transdermal, aerosol, buccal, sublingual,vaginal, parenteral, subcutaneous, pulmonary, or inhalation route ofadministration.
 10. The method according to claim 1, whereinadministering occurs by oral administration.
 11. A method of treating acondition in a subject, comprising: a. administering to a subject inneed thereof a therapeutically effective amount of a pharmaceuticallyacceptable acid addition salt of tolperisone, or hydrate thereof,comprising 5 ppm 2-methyl-1-(4-methylphenyl)-propenone (4-MMPO) or less,wherein said condition is at least one selected from the groupconsisting of muscle spasm, spasticity, neuropathic pain, painassociated with a nervous system disorder, lockjaw, dysmenorrhea,spastic syndrome, spastic paralysis, muscle soreness, myotonia,climacteric complaints, neurolatyrism, osteoarthritis, rheumatoidarthritis, rheumatic disease, fibromyalgia syndrome, occupationalstress, sport-related stress, back pain, spasticity caused byneurological diseases, multiple sclerosis, myelopathy,encephalomyelitis, stroke, muscular hypertension, muscular contracture,spinal automatism, obliterative vascular disease, obliterativearteriosclerosis, diabetic angiopathy, obliterative thromboangitis,Raynaud's disease, diffuse scleroderma, disorders due to injuredinnervation of the vessels, acrocyanosis, intermittent angioneuroticdysbasis, post-thrombotic venous and lymphatic circulation disorders,diabetic neuropathy, post-herpetic neuralgia, and crural ulcer.
 12. Themethod according to claim 11, wherein the condition is at least oneselected from the group consisting of: muscle spasm, spasticity,neuropathic pain, pain associated with a nervous system disorder,lockjaw, dysmenorrhea, spastic syndrome, spastic paralysis, musclesoreness, and back pain.
 13. The method according to claim 11, whereinthe condition is muscle spasm.
 14. The method according to claim 11,wherein the condition is spasticity.
 15. The method according to claim11, wherein the pharmaceutically acceptable acid addition salt oftolperisone, or hydrate thereof, comprises 4 ppm 4-MMPPO or less. 16.The method according to claim 11, wherein the pharmaceuticallyacceptable acid addition salt of tolperisone, or hydrate thereof,comprises 3 ppm 4-MMPPO or less.
 17. The method according to claim 11,wherein the pharmaceutically acceptable acid addition salt oftolperisone, or hydrate thereof, comprises 2 ppm 4-MMPPO or less. 18.The method according to claim 11, wherein the pharmaceuticallyacceptable acid addition salt of tolperisone comprises tolperisonehydrochloride.
 19. The method according to claim 11, wherein thepharmaceutically acceptable acid addition salt of tolperisone, orhydrate thereof, is formulated as a pharmaceutical compositioncomprising one or more excipients.
 20. The method according to claim 11,wherein the therapeutically effective amount of a pharmaceuticallyacceptable acid addition salt of tolperisone, or hydrate thereof, isbetween about 10 mg/day and 3,000 mg/day.
 21. The method according toclaim 11, wherein the therapeutically effective amount of apharmaceutically acceptable acid addition salt of tolperisone, orhydrate thereof, is between about 150 mg/day and 1,000 mg/day.
 22. Themethod according to claim 11, wherein administering occurs by an oral,intra-arterial, intrathecal, intraspinal, intramuscular,intraperitoneal, intravenous, intradermal, intranasal, inhalation,rectal, nasal, topical, transdermal, aerosol, buccal, sublingual,vaginal, parenteral, subcutaneous, pulmonary, or inhalation route ofadministration.
 23. The method according to claim 11, whereinadministering occurs by oral administration.
 24. A method of treatingmuscle spasms or spasticity in a subject, comprising: a. administeringto a subject in need thereof a therapeutically effective amount of apharmaceutical composition comprising tolperisone hydrochloride, saidpharmaceutical composition having less than 5 ppm2-methyl-1-(4-methylphenyl)-propenone (4-MMPO).
 25. The method accordingto claim 24, wherein the pharmaceutical composition has less than 4 ppm4-MMPPO.
 26. The method according to claim 24, wherein thepharmaceutical composition has less than 3 ppm 4-MMPPO.
 27. The methodaccording to claim 24, wherein the pharmaceutical composition has lessthan 2 ppm 4-MMPPO.
 28. The method according to claim 24, wherein thetherapeutically effective amount of said pharmaceutical composition isbetween about 10 mg/day and 3,000 mg/day.
 29. The method according toclaim 24, wherein said subject is treated for muscle spasms.
 30. Themethod according to claim 24, wherein said subject is treated forspasticity.